Small cell lung cancer (SCLC) is characterized by a high rate of growth, rapid dissemination, early metastasis and a dismal survival rate. Although chemotherapy works well initially in SCLC patients, they soon relapse and become unresponsive to chemotherapy. Our published data show that capsaicin (the spicy ingredient of chili peppers) displays anti-proliferative activity in a panel of human SCLC cell lines, in CAM and in athymic mice models. We also observed that the anti-proliferative activity of capsaicin is mediated by the transient receptor potential vanilloid (TRPV) family of ion channel receptors. The administration of capsaicin to athymic mice via dietary methods produced no discomfort or toxicity in mice. Furthermore, low concentrations of capsaicin could sensitize human SCLC cells to the growth-inhibitory effects of cisplatin in vitro. The present proposal will examine the co-operative effects of capsaicin and cisplatin in human SCLC tumors xenotransplanted into athymic mice. The central hypothesis of this proposal is that capsaicin will sensitize SCLC cells to apoptosis induced by chemotherapeutic drugs in athymic mice models. We also conjecture that the anti-proliferative activity of SCLCs is mediated via the TRPV receptor-subtypes. In addition, we intend to measure the oral bioavailability and tissue-distribution of capsaicin in mice. The studies in the present grant will lead to the identification of novel capsaicin-based combination therapies in human SCLCs. PUBLIC HEALTH RELEVANCE: Small cell lung cancer (SCLC) is a lethal malignancy characterized by rapid doubling time and very poor five-year survival rates. Although SCLC tumors are initially responsive to chemotherapy, they frequently relapse and then the tumor becomes insensitive to chemotherapy. The studies in the present grant propose that the nutritional agent capsaicin may be useful in combination therapies along with chemotherapeutic drugs for the treatment of SCLCs.